FMR1 premutation carriers exhibit mild cognitive impairment and have an increased rate of psychiatric disorders. Critically, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), which is characterized by progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, peripheral neuropathy and key neuropathological features. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. Given the high prevalence of the FMR1 premutation in the population (about 1/468 males) this is a significant health issue that affects a large number of individuals. There is currently no treatment for FXTAS and no empirically evaluated interventions to prevent or slow the disease progression. Importantly, no biological or behavioral markers are available for predicting which premutation carrier will develop FXTAS before the clinical symptoms appear. In the last funding period of our program of research (?Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers?) we have successfully followed FMR1 premutation carriers and age-matched controls for at least two, and in some cases 3 longitudinal time points, obtaining neuroimaging, neuropsychological, and molecular measurements as well as medical and neurological examinations. We have identified neuroimaging, behavioral and molecular markers that show promise for predicting, before the onset of clinical symptoms, which premutation carriers will convert to FXTAS, and for tracking changes during the early stages of disease. Ours remains the only prospective, longitudinal study of FMR1 premutation carriers being conducted, and understanding the prodrome of FXTAS remains critical for the early intervention and prevention of this neurodegenerative disease. For the current project, we will continue to collect longitudinal neuroimaging, neuropsychological and molecular data from our existing cohort and a new cohort of carriers and controls with an overarching goal to define the prodrome of FXTAS, refining our protocol in accordance with what we learned in the last five years, and adding biomarkers and clinically sensitive measures and assessments of lifestyle factors to better address hypotheses about risk and resilience in this population.